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Modulation of Doxorubicin Resistance by Valinomycin (NSC 122023) and Liposomal Valinomycin in Chinese Hamster Ovary Cells¹

Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365

Recently, we have reported that the toxicity of the membrane-active agent valinomycin (VM) can be reduced with maintenance and/or enhancement of its antitumor activity by incorporation in liposomes (S. S. Daoud and Juliano, Cancer Res., 46: 5518–5525, 1986). Since the underlying defect(s) in multidrug resistance reside mainly in the cell membrane, it seems reasonable to attempt to overcome multidrug resistance with membrane-active drugs. Here, we report on the in vitro restoration of Adriamycin (ADR) sensitivity in a resistant Chinese hamster ovary cell line (CH^RC5) by treatment with nontoxic doses of valinomycin or of liposomal valinomycin. During a 1-h drug exposure, the sensitivity of CH^RC5 to ADR was enhanced 21- to 28-fold when 20 or 40 nM VM was present, doses which are not toxic to CH^RC5 cells. At the same time, modest synergistic toxicity could be seen in the parent drug-sensitive cell line (AUX B1). At 100 nM VM, the sensitivity of CH^RC5 to ADR was restored to almost that of the sensitive AUX B1 cells. The effects of liposomal VM on ADR sensitivity were similar to the effects produced by free VM. At nontoxic doses and with continuous exposure of the drug, valinomycin was highly active in restoring ADR sensitivity in CH^RC5 cells. In cells treated for 72 h, valinomycin enhanced the sensitivity to ADR 208- to 250-fold in CH^RC5 and 3- to 5-fold in AUX B1 cells. Measurements of ADR uptake and efflux indicate that, unlike other multidrug resistance modifiers, valinomycin exerts its actions in modulating ADR resistance by mechanism(s) other than increasing intracellular accumulation of Adriamycin. The possible mechanisms of the restoration of ADR sensitivity by valinomycin are discussed.

¹ This work is supported in part by ASCI Grant IN-15-30 (S. S. D.) and National Cancer Institute Grant 47044 (R. L. J.).

² To whom requests for reprints should be addressed.

Received 9/20/88. Revised 12/21/88. Accepted 2/21/89.